Bupivacaine Formulation in a Polyorthoester Carrier

ABSTRACT

Effective treatments of pain, such as chronic pelvic pain, for extended periods of time are provided. The treatments include the administration of one or more drug depots intraspinally wherein the drug depots include an effective amount of bupivacaine formulated within a polyorthoester. By administration of one or more drug depots, one can relieve pain caused by diverse sources, including but not limited to chronic pelvic pain syndromes, spinal disc herniation (i.e. sciatica), spondilothesis, stenosis, discongenic back pain and joint pain, as well as pain that is incidental to surgery. In some embodiments, the relief can be for at least thirty days, at least sixty days, at least one hundred days or at least one hundred and thirty-five days.

This application claims the benefit of the filing date of U.S.Provisional Application No. 61/046,343 filed Apr. 18, 2008, entitled“Methods and Compositions for Treating Post-Operative Pain Comprising aLocal Anesthetic,” U.S. Provisional Application No. 61/046,201 filedApr. 18, 2008, entitled “Clonidine Formulations in a BiodegradablePolymer Carrier,” and U.S. Provisional Application No. 61/046,213 filedApr. 18, 2008, entitled “Medical Devices and Methods Including PolymersHaving Biologically Active Agents Therein,” all of which are herebyincorporated by reference thereto.

BACKGROUND

Pain control is of prime importance to anyone treating many differentdiseases and medical conditions. Proper pain relief imparts significantphysiological and psychological benefits to the patient. Not only doeseffective pain relief mean a smoother more pleasant recovery (e.g.,mood, sleep, quality of life, etc.) with earlier discharge frommedical/surgical/outpatient facilities, but it may also reduce theprobability of the acute pain state progressing to a chronic painsyndrome.

Pain serves an important biological function. It signals the presence ofdamage or disease within the body and is often accompanied byinflammation (redness, swelling, and/or burning). There are two types ofpain based on temporal classification: acute pain and chronic pain.Acute pain refers to pain experienced when tissue is being damaged or isdamaged. Acute pain serves at least two physiologically advantageouspurposes. First, it warns of dangerous environmental stimuli (such ashot or sharp objects) by triggering reflexive responses that end contactwith the dangerous stimuli. Second, if reflexive responses do not avoiddangerous environmental stimuli effectively, or tissue injury orinfection otherwise results, acute pain facilitates recuperativebehaviors. For example, acute pain associated with an injury orinfection encourages an organism to protect the compromised area fromfurther insult or use while the injury or infection heals. Once thedangerous environmental stimulus is removed, or the injury or infectionhas resolved, acute pain, having served its physiological purpose, ends.As contrasted to acute pain, in general, chronic pain serves nobeneficial purpose. Chronic pain results when pain associated with aninjury or infection continues in an area once the injury or infectionhas resolved. Chronic pain may involve injury and changes to the nervoussystem which is referred to as neuropathic pain. Chronic pain may alsoinvolve persistent activation of physiological or nociceptive pathwaysif the insult is prolonged such as pain associated with certain types ofcancer.

There are many painful diseases or conditions that require proper painand/or inflammation control, including but not limited to rheumatoidarthritis, osteoarthritis, spinal disc herniation (i.e., sciatica),carpal/tarsal tunnel syndrome, lower back pain, lower extremity pain,upper extremity pain, cancer, tissue pain and pain associated withinjury or repair of cervical, thoracic, and/or lumbar vertebrae orintervertebral discs, rotator cuff, articular joint, TMJ, tendons,ligaments, muscles, spondilothesis, stenosis, discogenic back pain, andjoint pain or the like.

One category of chronic pain is chronic pelvic pain syndromes. Chronicpelvic pain may occur in both men and women of all ages and results froma variety of injuries and disorders. It is a common and debilitatingproblem that can significantly impair the quality of life of the patientsuffering from it. Chronic pelvic pain occurs in the pelvic or lowerabdominal region and can last for six months or longer.

In men, chronic pelvic pain may result from chronic idiopathicprostatitis (also referred to as nonbacterial prostatitis or chronicpelvic pain syndrome), chronic bacterial prostatitis or interstitialcystitis where the symptoms typically include in addition to pelvicpain, urinary urgency and frequency, sexual dysfunction and in mostcases patients have a hypertonic pelvic floor muscles upon physicalexamination. The most common treatment for these disorders involvespharmacologic treatments typically orally administered such asantibiotics, anti-inflammatory agents, alpha blockers, anti-spasmodics,analgesics, and muscle relaxants. Alpha blockers have successfullytreated symptoms of prostatitis in some patients, although theimprovements have been modest and adverse event rates have beensignificant. Oral muscle relaxants may help decrease pelvic floor toneoften associated with dose-limiting side effects which limit theirusefulness.

Other types of chronic pelvic pain experienced by men include chronictesticular pain (CTP), post vasectomy pain, genitofemoral neuralgia andother pain originating from the testicles, groin, or abdomen. Theincidence of patients with CTP, also referred to as orchialgia,orchidynia, or chronic scrotal pain, is large and may be caused byon-going inflammation of the testicle (orchitis) or epididymis(epdidymitis), trauma, tumors, hernia, torsion (twisting of thetesticle), varicocele, hydrocele, spermatocele polyarteritis nodosa, andprevious surgical interventions such as vasectomy and hernia surgery.

Typically, testicle removal and spermatic cord denervation proceduresare used to treat CTP. In spermatic cord denervation procedures, nervesin or adjacent to the spermatic cord, i.e., the genitofemoral nerve orsympathetic nerves, are severed or permanently removed. Such proceduresmay result in permanent and substantial pain relief regardless of theorigin of pain. However, severing or removing these nerves may result inloss of sensation in the testicle and/or scrotum, loss of thecremasteric reflex which may cause fertility issues, and even loss ofblood flow causing the testicle to die. Therapeutic nerve blocks mayalso be used to treat CTP, but generally only relieve pain temporarily.Chronic pelvic pain is also a common medical problem affecting womentoday. Sources of pain may include injury to nerves resulting fromsurgical procedures, non-surgical conditions, vulvodynia which can bevery debilitating but has no obvious source, and interstitial cystitis(painful bladder syndrome). Surgical procedures that may injure nervesin the pelvic region resulting in pelvic pain may include urologicaloperations in the pelvic area, gynecological surgery, and hysterectomy.Non-surgical conditions which cause pain in women include adhesions,endometriosis, and pelvic congestion. Irritable bowel syndrome may alsobe considered a chronic pelvic pain condition. Surgical procedures aimedat removing the suspected painful bladder have generally beenunsuccessful and often result in worsening of the pain state. Thisresult suggests that the chronic pain state has extended beyond theperipheral organ and may involve central sensitization with the spinalcord that receives sensory input from the peripheral organs.

One known class of pharmaceuticals used to treat pain is opioids. Thisclass of compounds is well-recognized as being among the most effectivetype of drugs for controlling pain, such as post-operative pain.Unfortunately, because opioids are administered systemically, theassociated side effects raise significant concerns, including disablingthe patient, depressing the respiratory system, constipation, andpsychoactive effects such as sedation and euphoria, thereby institutinga hurdle to recovery and regained mobility. Consequently, physicianstypically limit the administration of opioids to within the firsttwenty-four hours post-surgery. Although opioids may be used to managesevere episodes of chronic pelvic pain, chronic opioid use may beassociated with the development of tolerance leading to the need forhigher doses to produce sustained analgesic effects. They may also beassociated with addiction.

One pharmaceutical agent that is well known to the medical profession isbupivacaine, which is widely recognized as an amide-type localanesthetic that blocks neuronal sodium channels. In general,bupivacaine, also referred to as1-butyl-N-(2,6-dimethylphenyl)piperidine-2-carboxamide (C₁₈H₂₈N₂O), maybe represented by the following chemical structure:

Bupivacaine has been used historically to produce both local andregional anesthesia. It can be administered directly into the tissuewhere the surgery will be performed, around a specific nerve thatprovides sensory innervation to the tissue or intraspinally (epidural orintrathecal) to treat the spinal cord and provide analgesia for pelvicoperations, child delivery, and post surgical recovery. Generally whenadministered as a solution, the effects of bupivacaine generally lastbetween 4 to 6 hours. Thus, there is a need to develop effectiveformulations of this compound for this application that providesustained release of bupivacaine thereby prolonged pain relief.

SUMMARY

Compositions and methods are provided comprising bupivacaine that areadministered in order to treat prolonged episodes of pain, such as thatassociated with chronic pelvic pain conditions. The compositions andmethods of the present invention may also for example be used to treatpain due to a spinal disc herniation (i.e., sciatica), spondilothesis,stenosis, osteoarthritis, carpal/tarsal tuunel syndrome, tendonitis,temporomandibular joint disorder (TMJ) and discogenic back pain andjoint pain, as well as pain that accompanies or follows surgery.

In one embodiment, an implantable drug depot useful for reducing,preventing or treating pain, such as chronic pelvic pain, in a patientin need of such treatment is provided. The drug depot comprises apolyorthoester (“POE”) and bupivacaine. The drug depot is administeredintraspinally to reduce, prevent or treat pain. The drug depot iscapable of releasing bupivacaine in an amount between 5 and 50 mg perday for a period of 30 to 135 days. Bupivacaine may be present in anamount of about 1 to about 50 wt. % of the drug depot.

In another embodiment, a pharmaceutical formulation comprisingbupivacaine, wherein the bupivacaine comprises from about 1 wt. % toabout 50 wt. %, 10 wt. % to about 40 wt. % or about 20 wt. % to about 35wt. % of the formulation, and a polyorthoester is provided. Thepharmaceutical composition may for example, be part of a drug depot. Thedrug depot may: (i) consist of only the bupivacaine and thepolyorthoester; or (ii) consist essentially of the bupivacaine and thepolyorthoester; or (iii) comprise the bupivacaine, the polyorthoesterand one or more other active ingredients, surfactants, excipients orother ingredients or combinations thereof. When there are other activeingredients, surfactants, excipients or other ingredients orcombinations thereof in the formulation, in some embodiments these othercompounds or combinations thereof comprise less than 20 wt. %, less than19 wt. %, less than 18 wt. %, less than 17 wt. %, less than 16 wt. %,less than 15 wt. %, less than 14 wt. %, less than 13 wt. %, less than 12wt. %, less than 11 wt. %, less than 10 wt. %, less than 9 wt. %, lessthan 8 wt. %, less than 7 wt. %, less than 6 wt. %, less than 5 wt. %,less than 4 wt. %, less than 3 wt. %, less than 2 wt. %, less than 1 wt.% or less than 0.5 wt. % of the drug depot. The drug depot is capable ofreleasing bupivacaine over a period of at least thirty days.

According to another embodiment, there is an implantable drug depot forreducing, preventing or treating pain, such as chronic pelvic pain, in apatient in need of such treatment, the implantable drug depot comprisingbupivacaine in an amount of from about 1 wt. % to about 50 wt. % of thedrug depot and a polyorthoester in an amount of at least 50 wt. % of thedrug depot.

In still another embodiment, a method for treating pain, such as chronicpelvic pain, is provided. The method comprises implanting a drug depotintraspinally in an organism to reduce, prevent or treat the pain. Thedrug depot comprises bupivacaine and a polyorthoester. Bupivacaine ispresent in an amount from about 1 wt. % to about 50 wt. %, about 10 wt.% to about 40 wt. % or about 20 wt. % to about 35 wt. % of the drugdepot.

In still yet another embodiment, an implantable drug depot comprisingbupivacaine and a polyorthoester is provided. The drug depot is capableof releasing an initial bolus dose of the bupivacaine at a site beneaththe skin of a patient, and the drug depot is capable of releasing asustained release dose of an effective amount of the bupivacaine over asubsequent period of 30 to 135 days. The bupivacaine comprises about 1wt. % to about 50 wt. % of the total wt. % of the drug depot and thepolyorthoester comprises at least about 50 wt. % of the drug depot.

In another embodiment, a method of making an implantable drug depot isprovided. The method comprises combining a polyorthoester and atherapeutically effective amount of bupivacaine and forming animplantable drug depot from the combination.

In various embodiments, bupivacaine may be in the form of a base.Alternatively, bupivacaine may be in the form of a salt. One example ofa salt is a hydrochloride salt. Bupivacaine may also be in the form of amixture of a hydrochloride salt and free base.

Bupivacaine in the various embodiments is capable of being released inan amount between 5 and 50 mg per day for a period of 30 to 180 days.The drug depot in the various embodiments is capable of releasing about5% to about 100% of the bupivacaine relative to a total amount of thebupivacaine loaded in the drug depot over a period of 30 to 200 daysafter the drug depot is implanted in the organism.

The polyorthoester in the various embodiments may comprise about 50 wt.% to about 99 wt. % of the total wt. % of the drug depot. Thepolyorthoester is capable of degrading or degrades in 200 days or lessafter the drug depot is implanted at a site.

The drug depot in the various embodiments may further comprise one ormore of polyaspirin, polyphosphazene, polyanhydride; polyketal,collagen, starch, pre-gelatinized starch, hyaluronic acid, chitosan,gelatin, alginate, albumin, fibrin, vitamin E analog, d-alpha tocopherylsuccinate, poly-ε-caprolactone, dextran, polyvinylpyrrolidone, polyvinylalcohol, PEGT-PBT copolymer, PEO-PPO-PEO, sucrose acetate isobutyrate, adifferent polyorthoester or a combination thereof.

The drug depot in various embodiments may comprise a radiographic markeradapted to assist in radiographic imaging. The radiographic marker maycomprise barium, bismuth, tantalum, tungsten, iodine, calcium phosphate,and/or metal beads.

The drug depot in various embodiments may comprise a hydrophilic agent,such as baclofen, to help control release and/or provide aco-therapeutic effect.

The drug depot in various embodiments is capable of releasing between 5and 50 milligrams (mg) per day of bupivacaine to reduce, prevent ortreat pain, such as chronic pelvic pain.

The target site in the various embodiments comprises the lumbosacralepidural space or at least one muscle, ligament, tendon, cartilage,spinal disc, spinal foraminal space near the spinal nerve root, facet orsynovial joint, or spinal canal.

The pain may be associated with pelvic pain such as interstitialcystitis or chronic nobacterial prostatitis, hernia repair, orthopedicor spine surgery or a combination thereof The surgery may bearthroseopic surgery, an excision of a mass, hernia repair, spinalfusion, thoracic, cervical, or lumbar surgery, pelvic surgery or acombination thereof.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims and accompanying drawings where:

FIG. 1 is a graphic representation of the cumulative in-vitro release ofbupivacaine for the microsphere formulation of Example 2 in a phosphatebuffered saline solution.

FIG. 2 is a graphic representation of the release rate of bupivacainefor the microsphere formulation of Example 2 in a phosphate bufferedsaline solution.

FIG. 3 is a graphic representation of the cumulative in-vitro release ofbupivacaine for the microsphere formulation of Example 2 in a phosphatebuffered saline solution containing 0.5% SDS.

FIG. 4 is a graphic representation of the release rate of bupivacainefor the microsphere formulation of Example 2 in a phosphate bufferedsaline solution containing 0.5% SDS.

FIG. 5 is a graphic representation of epidural infusion of bupivacainein rats treated with an intravesical infusion of saline. Baselinebladder activity was measured before epidural drug treatment asdescribed in Example 4. The columns and error bars represent the meanand SEM values of 10 rats per group. Asterisks indicate statisticallysignificant dose effects compared to baseline as determined by post-hocDunnett Multiple Comparison Test.

FIG. 6 is a graphic representation of epidural infusion of bupivacainein rats treated with an intravesical infusion of acetic acid asdescribed in Example 4. Baseline bladder activity was measured beforeepidural drug treatment. The columns and error bars represent the meanand SEM values of 10 rats per group. Asterisks indicate statisticallysignificant dose effects compared to baseline as determined by post-hocDunnett Multiple Comparison Test.

It is to be understood that the figures are not drawn to scale. Further,the relation between objects in a figure may not be to scale, and may infact have a reverse relationship as to size. The figures are intended tobring understanding and clarity to the structure of each object shown,and thus, some features may be exaggerated in order to illustrate aspecific feature of a structure.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Definitions

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

A “drug depot” is the composition in which the bupivacaine isadministered to the body. Thus, a drug depot may comprise a physicalstructure to facilitate implantation and retention in a target site. Thedrug depot may also comprise the drug itself. The term “drug” as usedherein is generally meant to refer to any substance that alters thephysiology of a patient. The term “drug” may be used interchangeablyherein with the terms “therapeutic agent,” “therapeutically effectiveamount,” and “active pharmaceutical ingredient” or “API.” It will beunderstood that unless otherwise specified a “drug” formulation mayinclude more than one therapeutic agent, wherein exemplary combinationsof therapeutic agents include a combination of two or more drugs. Thedrug depot provides a concentration gradient of the therapeutic agentfor delivery to the target site.

“Target site” as used herein is used to refer to an area of the body towhich the drug is administered. Target sites desirably used with themethods of this invention include specific regions within the spinalcanal. As used herein, the term “spinal region” includes the spinalcanal (including the spinal cord, intrathecal space, dura, epiduralspace, etc.), vertebrae, spinal discs, nerve roots, and the ligaments,tendons and muscles in between and surrounding the vertebrae. In oneembodiment of the invention, the target site is epidural. In otherembodiments the target site is in the intrathecal or peridural spaces ofthe spinal region. The target sites for the administration of a drug toalleviate pelvic pain in subjects also experiencing bladder or pelvicfloor disorders is desirably in the epidural, peridural or intrathecalspaces in the spinal region between the sacrum and/or coccyx, desirablybetween Co1 and L1, between S5 and S1, between S2 and L1, or between T10and S4. In one embodiment, the target site is the spinal region that maybe accessed through the sacral hiatus or the sacral foramen.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain or spasticity, improvement in the condition throughmuscle relaxation, etc. The dosage administered to a patient can be assingle or multiple doses depending upon a variety of factors, includingthe drug's administered pharmacokinetic properties, the route ofadministration, patient conditions and characteristics (sex, age, bodyweight, health, size, etc.), extent and duration of symptoms, concurrenttreatments, frequency of treatment and the effect desired. In someembodiments, the formulation is designed for sustained release. In otherembodiments, the formulation comprises one or more immediate releasesurfaces and one or more sustained release surfaces.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

As used herein, “biodegradable” and “bioerodible” are usedinterchangeably and are intended to broadly encompass materialsincluding, for example, those that tend to break down upon exposure tophysiological environments. Biodegradable and/or bioerodible polymersknown in the art include, for example, linear aliphatic polyesterhomopolymers (e.g., polyglycolide, polylactide, polycaprolactone, andpolyhydroxybutyrate) and copolymers (e.g., poly(glycolide-co-lactide),poly(glycolide-co-caprolactone),poly(glycolide-co-trimethylenecarbonate), poly(lactic acid-co-lysine),poly(lactide-co-urethane), poly(ester-co-amide)); polyanhydrides;polyketals; and poly(orthoesters). “Biocompatible” means that the depotwill not cause substantial tissue irritation or necrosis at the targettissue site.

The phrases “sustained release” and “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually release an amountof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release is intended to encompass release thatoccurs as the result of biodegradation in vivo of the drug depot, or amatrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s).

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or action of the drug.

The two types of formulations (sustain release and immediate release)may be used in conjunction. The sustained release and immediate releasemay be in one or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example, a bolus or immediate release formulation of bupivacaine maybe placed at or near the target site and a sustain release formulationmay also be placed at or near the same site. Thus, even after the bolusbecomes completely exhausted, the sustain release formulation wouldcontinue to provide the active ingredient for the intended tissue.

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first twenty-fourhours after implantation. “Initial burst” or “burst effect” refers tothe release of therapeutic agent from the depot during the firsttwenty-four hours after the depot comes in contact with a biologicalfluid (e.g., interstitial fluid, synovial fluid, cerebrospinal fluid,etc.). The “burst effect” is believed to be due to the increased releaseof therapeutic agent from the depot. In alternative embodiments, thedepot is designed to avoid this initial burst effect.

“Treating” or “treatment” of a disease or condition refers to executinga protocol that may include administering one or more drugs to a patient(human, or other mammal), in an effort to alleviate or eliminate signsor symptoms of the disease or condition. Alleviation can occur prior tosigns or symptoms of the disease or condition appearing, as well asafter their appearance. Thus, treating or treatment includes preventingor prevention of disease or undesirable condition. In addition, treatingor treatment does not require complete alleviation of signs or symptoms,does not require a cure, and specifically includes protocols that haveonly a marginal effect on the patient.

“Localized” delivery includes delivery where one or more drugs aredeposited within or near a tissue, for example, a nerve root of thenervous system or a region of the spinal cord, or in close proximity(within about 0.1 cm, or preferably within about 1.0 cm, for example)thereto.

The term “mammal” refers to organisms from the taxonomic class“mammalia,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

The phrase “pain management medication” includes one or more therapeuticagents that are administered to prevent, alleviate or remove painentirely. These include anti-inflammatory agents, muscle relaxants,analgesics, anesthetics, narcotics, and so forth, and combinationsthereof.

The phrase “release rate” refers to the percentage of active ingredientthat is released over fixed units of time, e.g., mcg/hr, mcg/day, 10%per day for ten days, etc. As persons of ordinary skill know, a releaserate profile may, but need not, be linear. By way of a non-limitingexample, the drug depot may be a ribbon-like fiber that releases thebupivacaine over a period of time.

The term “solid” is intended to mean a rigid material, while,“semi-solid” is intended to mean a material that has some degree offlexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

The term “gel” is intended to mean a semi-solid material that may beflowable upon application to the target site, then may harden orincrease in viscosity upon delivery.

“Targeted delivery system” provides delivery of one or more drug depots,gels or depots dispersed in the gel having a quantity of therapeuticagent that can be deposited at or near the target site as needed fortreatment of pain, inflammation or other disease or condition.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

The headings below are not meant to limit the disclosure in any way;embodiments under any one heading may be used in conjunction withembodiments under any other heading.

Bupivacaine

When referring to bupivacaine, the active ingredient may be in the saltform or the base form (e.g., free base). In various embodiments, if itis in the base form, it may be combined with a polymer such as apolyorthoester under conditions in which there is not significantpolymer degradation. By way of a non-limiting example, when formulatingbupivacaine with a polyorthoester, it may be desirable to use thebupivacaine base formulation.

Further, bupivacaine may be in the salt form and one well-knowncommercially available salt for bupivacaine is its hydrochloride salt.Some other examples of potentially pharmaceutically acceptable saltsinclude those salt-forming acids that do not substantially increase thetoxicity of a compound, such as, salts of mineral acids such ashydriodic, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuricacids, as well as salts of organic acids such as tartaric, acetic,citric, malic, benzoic, glycolic, gluconic, gulonic, succinic,arylsulfonic, e.g., p-toluenesulfonic acids, and the like.

Bupivacaine may be administered with a muscle relaxant. Exemplary musclerelaxants include by way of example and not limitation, alcuroniumchloride, atracurium bescylate, baclofen, carbamate, carbolonium,carisoprodol, chlorphenesin, chlorzoxazone, cyclobenzaprine, dantrolene,decamethonium bromide, fazadinium, gallamine triethiodide,hexafluorenium, meladrazine, mephensin, metaxalone, methocarbamol,metocurine iodide, pancuronium, pridinol mesylate, styramate,suxamethonium, suxethonium, thiocolchicoside, tizanidine, tolperisone,tubocuarine, vecuronium, midazolam or combinations thereof.

Bupivacaine may also be administered with other suitable analgesicagents that include, but are not limited to, acetaminophen, clonidine,opioid analgesics such as buprenorphine, butorphanol, dextromoramide,dezocine, dextropropoxyphene, diamorphine, fentanyl, alfentanil,sufentanil, hydrocodone, hydromorphone, ketobemidone, levomethadyl,mepiridine, methadone, morphine, nalbuphine, opium, oxycodone,papaveretum, pentazocine, pethidine, phenoperidine, piritramide,dextropropoxyphene, remifentanil, tilidine, tramadol, codeine,dihydrocodeine, meptazinol, dezocine, eptazocine, and nonopioidanalgesics such as flupirtine, amitriptyline, carbamazepine, gabapentin,pregabalin, or a combination thereof.

Bupivacaine may also be administered with non-active ingredients. Thesenon-active ingredients may have multi-functional purposes including thecarrying, stabilizing and controlling of the release of the therapeuticagent(s). The sustained release process, for example, may be by asolution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable.

Exemplary excipients that may be formulated with bupivacaine in additionto the biodegradable polymer include but are not limited to MgO, PEG,mPEG, Span-65, Span-85, pluronic F127, TBO-Ac, sorbital, cyclodextrin,maltodextrin, maltose, mannitol, pluronic F68, CaCl₂, and combinationsthereof. In some embodiments, the excipients comprise from about 0.001wt. % to about 50 wt. % of the formulation. In some embodiments, theexcipients comprise from about 0.001 wt. % to about 40 wt. % of theformulation. In some embodiments, the excipients comprise from about0.001 wt. % to about 30 wt. % of the formulation. In some embodiments,the excipients comprise from about 0.001 wt. % to about 20 wt. % of theformulation. In some embodiments, the excipients comprise from about 0.1wt. % to about 10 wt. % of the formulation. In some embodiments, theexcipients comprise from about 0.001 wt. % to about 2 wt. % of theformulation. In some embodiments, the excipients comprise from about 0.1wt. % to about 5 wt. % of the formulation. In some embodiments, theexcipients comprise from about 0.1 wt. % to about 2 wt. % of theformulation.

In various embodiments, the depot may comprise a biodegradablepolyorthoester. The mechanism of the degradation process of thepolyorthoester can be hydrolytic. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion). Polyorthoester materials can be obtainedfrom A.P. Pharma, Inc. (Redwood City, Calif.) or through the reaction ofa bis(ketene acetal) such as3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) withsuitable combinations of diol(s) and/or polyol(s) such as1,4-trans-cyclohexanedimethanol and 1,6-hexanediol or by any otherchemical reaction that produces a polymer comprising orthoestermoieties. Some exemplary polyorthoester materials suitable for use inthe present invention are described in U.S. Patent ApplicationPublication Number 2008/0033140, entitled “Poly(Orthoester) Polymers,and Methods of Making and Using Same” which is hereby incorporated byreference in its entirety.

In some embodiments, the drug depot may not be completely biodegradable.For example, the drug depot may comprise polyorthoester and one of moreof the following: polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. Typically, these types of drug depots may need tobe removed after a certain amount of time.

In various embodiments, the depot may comprise a bioerodable, abioabsorbable, and/or a biodegradable biopolymer in addition to apolyorthoester that may provide immediate release, or sustained releaseof the bupivacaine. The biopolymer may also include one or more of thefollowing biopolymers: polyaspirins, polyphosphazenes, polyanhydrides;polyketals, collagen, starch, pre-gelatinized starch, hyaluronic acid,chitosans, gelatin, alginates, albumin, fibrin, vitamin E analogs, suchas alpha tocopheryl acetate, d-alpha tocopheryl succinate,poly-ε-caprolactone, dextrans, polyvinylpyrrolidone, polyvinyl alcohol(PVA), PEGT-PBT copolymer (PolyActive®), PEO-PPO-PEO (Pluronics®),Poloxamer 407, SAIB (sucrose acetate isobutyrate), a differentpolyorthoester or other biodegradeable polymer or combinations thereof.As persons of ordinary skill are aware, mPEG may be used as aplasticizer for a POE, but other polymers/excipients may be used toachieve the same effect. mPEG imparts malleability to the resultingformulations.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide, sodium phosphate,magnesium oxide or magnesium carbonate; degradation/release modifiers;drug release adjusting agents; emulsifiers; preservatives such asbenzalkonium chloride, chlorobutanol, phenylmercuric acetate andphenylmercuric nitrate, sodium bisulfate, sodium bisulfite, sodiumthiosulfate, thimerosal, methylparaben, polyvinyl alcohol andphenylethyl alcohol; solubility adjusting agents; stabilizers; and/orcohesion modifiers. If the depot is to be placed in the spinal area, invarious embodiments, the depot may comprise sterile preservative freematerial.

The depot can be of different sizes, shapes and configurations. Thereare several factors that can be taken into consideration in determiningthe size, shape and configuration of the drug depot. For example, boththe size and shape may allow for ease in positioning the drug depot atthe target tissue site that is selected as the implantation or injectionsite. In some embodiments, the shape and size of the system should beselected so as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a pellet, a cylinder such as a rod or fiber, aflat surface such as a disc, film or sheet (e.g., ribbon-like) or thelike. Flexibility may be a consideration so as to facilitate placementof the drug depot. In one embodiment, the drug depot has the shape of aribbon and has a length of from about 10 mm to 200 mm. In anotherembodiment, the drug depot is in the form of microspheres having anaverage diameter from about 1 micron to about 500 microns, morespecifically from about 1 micron to about 250 microns, morespecifically, from about 1 micron to about 150 microns, and morespecifically from about 10 microns to about 100 microns.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, bismuth, tantalum, tungsten, iodine, calcium phosphate, and/ormetal beads or particles. In various embodiments, the radiographicmarker could be a spherical shape or a ring around the depot.

In some embodiments, the drug depot has pores that control release ofthe drug from the depot. The pores allow fluid into the depot todisplace and/or dissolve the drug.

Gel

In various embodiments, bupivacaine and polyorthoester are administeredwith or in a gel. The gel may have a pre-dosed viscosity in the range ofabout 1 to about 200,000 centipoise (cP), 100 to about 20,000 cP, or 500to about 10,000 cP. After the gel is administered to the target site,the viscosity of the gel will increase and the gel will have a modulusof elasticity (Young's modulus) in the range of about 1×10² to about6×10⁵ dynes/cm², or 2×10⁴ to about 5×10⁵ dynes/cm², or 5×10⁴ to about5×10⁵ dynes/cm².

The gel may be of any suitable type, as previously indicated, and shouldbe sufficiently viscous so as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”or adhere to the targeted tissue site or conform to the target tissuespace. The gel may, for example, solidify upon contact with the targetedtissue or after deployment from a targeted delivery system. The targeteddelivery system may be, for example, a syringe, a catheter, sheath,needle or cannula or any other suitable device. The targeted deliverysystem may inject the gel into or on the targeted site. The therapeuticagent may be mixed into the gel prior to the gel being deployed at thetargeted site. In various embodiments, the gel may be part of atwo-component delivery system and when the two components are mixed, achemical process is activated to form the gel and cause it to stick orto adhere to the target site.

The gel may harden or stiffen after delivery. Typically, hardening gelformulations may have a pre-dosed modulus of elasticity in the range ofabout 1×10² to about 3×10⁵ dynes/cm², or 2×10² to about 2×10⁵ dynes/cm²,or 5×10² to about 1×10⁵ dynes/cm². The post-dosed hardening gels (afterdelivery) may have a rubbery consistency and have a modulus ofelasticity in the range of about 1×10⁴ to about 2×10⁶ dynes/cm², or1×10⁵ to about 7×10⁵ dynes/cm², or 2×10⁵ to about 5×10⁵ dynes/cm².

If the gel includes bupivacaine and a polyorthoester, the polyorthoesterconcentration may affect the rate at which the gel hardens (e.g., a gelwith a higher concentration of polymer may coagulate more quickly thangels having a lower concentration of polymer). In various embodiments,when the gel hardens, the resulting matrix is solid but is also able toconform to the irregular surface of the target site.

The percentage of polyorthoester present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances. In some embodiments, the polyorthoester comprises 20 wt.% to 90 wt. % of the formulation.

In various embodiments, the molecular weight of the polymers that makeup the gel can be varied by many methods known in the art. The choice ofmethod to vary molecular weight is typically determined by thecomposition of the gel (e.g. polymer, versus non-polymer). For example,in various embodiments, the degree of polymerization can be controlledby varying the amount of polymer initiators (e.g. benzoyl peroxide),organic solvents or activator (e.g. DMPT), crosslinking agents,polymerization agent, reaction time and/or by including chain transferor chain terminating agents.

The gel can vary from low viscosity, similar to that of water, to highviscosity, similar to that of a paste, depending on the molecular weightand concentration of the polyorthoester used in the gel. The viscosityof the gel can be varied such that the composition can be applied to apatient's tissues by any convenient technique, for example, by brushing,dripping, injecting, or painting. Different viscosities of the gel areselected to conform to the technique used to deliver the composition.

The gel may optionally have a viscosity enhancing agent such as, forexample, hydroxypropyl cellulose, hydroxypropyl methylcellulose,hydroxyethyl methylcellulose, carboxymethylcellulose and salts thereofCarbopol, poly-(hydroxyethylmethacrylate),poly-(methoxyethylmethacrylate), poly(methoxyethoxyethyl methacrylate),polymethylmethacrylate (PMMA), methylmethacrylate (MMA), gelatin,polyvinyl alcohols, propylene glycol, mPEG, PEG 200, PEG 300, PEG 400,PEG 500, PEG 600, PEG 700, PEG 800, PEG 900, PEG 1000, PEG 1450, PEG3350, PEG 4500, PEG 8000 or combinations thereof.

Drug Delivery

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a catheter or a “cannula”,“trocar” or “needle” that can be a part of a drug delivery device e.g.,a syringe, a gun drug delivery device, or any medical device suitablefor the application of a drug to a targeted site. The catheter, cannula,trocar or needle of the drug depot device is designed to cause minimalphysical and psychological trauma to the patient.

Catheters, cannulas, trocars or needles include tubes that may be madefrom materials, such as for example, polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics or combinations thereof. The cannula or needle may optionallyinclude one or more tapered regions. In various embodiments, the cannulaor needle may be beveled. The cannula or needle may also have a tipstyle vital for accurate treatment of the patient depending on the sitefor implantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The diameter of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the diameter includes, but is not limited to, from about0.05 to about 1.655 (mm). The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 22 gauge. In various embodiments,the gauge of the needle or cannula is about 18 to about 22 gauge. Insome embodiments, the needle or cannula may include two lumens: one foradministering the drug depot and a second for administering aradiocontrast agent. This allows both to be administered without havingto reposition the needle.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include, but are not limited to, barium, bismuth, tantalum,tungsten, iodine, gold, calcium, and/or metal beads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualized by ultrasound,fluoroscopy, X-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot, and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requireindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to implant the drug depot. The kit may include the drug depotdevice in a first compartment. The second compartment may include acanister holding the drug depot and any other instruments needed for thelocalized drug delivery. A third compartment may include gloves, drapes,wound dressings and other procedural supplies for maintaining sterilityof the implanting process, as well as an instruction booklet. A fourthcompartment may include additional cannulas and/or needles. A fifthcompartment may include an agent for radiographic imaging. Each tool maybe separately packaged in a plastic pouch that is radiation sterilized.A cover of the kit may include illustrations of the implanting procedureand a clear plastic cover may be placed over the compartments tomaintain sterility.

In one embodiment, the drug depot is desirably delivered to thelumbosacral spinal region. A depot may be delivered to that space via adrug delivery catheter. The techniques for such delivery method are wellknown in the art. In one embodiment, the Seldinger technique is used andan introducer having a lumen is used to enter the spinal space throughone of the sacral hiatuses or sacral foramina, a guidewire is passedthrough the introducer, the introducer is removed and the catheter isadvanced over the wire until it is in position for drug delivery.

In various embodiments, to administer the gel having the drug depotdispersed therein to the desired site, first the cannula or needle canbe inserted through the skin and soft tissue down to the target site andthe gel administered at or near the target site. In those embodimentswhere the drug depot is separate from the gel, first the cannula orneedle can be inserted through the skin and soft tissue down to the siteof injection and one or more base layer(s) of gel can be administered tothe target site. Following administration of the one or more baselayer(s), the drug depot can be implanted on or in the base layer(s) sothat the gel can hold the depot in place or reduce migration. Ifrequired, a subsequent layer or layers of gel can be applied on the drugdepot to surround the depot and further hold it in place. Alternatively,the drug depot may be implanted first and then the gel placed around thedrug depot to hold it in place. By using the gel, accurate and preciseimplantation of a drug depot can be accomplished with minimal physicaland psychological trauma to the patient. The gel also avoids the need tosuture the drug depot to the target site reducing physical andpsychological trauma to the patient.

The formulations of the present application may be used as medicamentsin the form of pharmaceutical preparations. The preparations may beformed in an administration with a suitable pharmaceutical carrier thatmay be solid or liquid and organic or inorganic, and placed in theappropriate form for parenteral or other administration as desired. Aspersons of ordinary skill are aware, known carriers include but are notlimited to water, gelatin, lactose, starches, stearic acid, magnesiumstearate, talc, vegetable oils, benzyl alcohols, gums, waxes, propyleneglycol, polyalkylene glycols and other known carriers for medicaments.

In some embodiments, bupivacaine and polyorthoester formulations aresuitable for parenteral administration. The term “parenteral” as usedherein refers to modes of administration that bypass thegastrointestinal tract, and include for example, intravenous,intramuscular, continuous or intermittent infusion, intraperitoneal,intrastemal, subcutaneous, intra-operatively, intrathecally,intradiskally, peridiskally, epidurally, perispinally, intraarticularinjection or combinations thereof In some embodiments, the injection isintrathecal, which refers to an injection into the spinal canal(subarachnoid space surrounding the spinal cord).

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing a solvent and abiocompatible polymer are combined and placed in a mold of the desiredsize and shape. In this way, polymeric regions, including barrierlayers, lubricious layers, and so forth can be formed. If desired, thesolution can further comprise, one or more of the following: bupivacaineand other therapeutic agent(s) and other optional additives such asradiographic agent(s), etc. in dissolved or dispersed form. This resultsin a polymeric matrix region containing these species after solventremoval. In other embodiments, a solution containing solvent withdissolved or dispersed therapeutic agent is applied to a pre-existingpolymeric region, which can be formed using a variety of techniquesincluding solution processing and thermoplastic processing techniques,whereupon the therapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming a depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thepolyorthoester and one or more of the following: bupivacaine, optionaladditional therapeutic agent(s), radiographic agent(s), and so forth.The resulting mixture is then shaped into an implantable drug depot. Themixing and shaping operations may be performed using any of theconventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures andlor mechanical shear that are associated with suchprocessing. For example, bupivacaine may undergo substantial degradationunder ordinary thermoplastic processing conditions. Hence, processing ispreferably performed under modified conditions, which prevent thesubstantial degradation of the therapeutic agent(s). Although it isunderstood that some degradation may be unavoidable during thermoplasticprocessing, degradation is generally limited to 10% or less. Among theprocessing conditions that may be controlled during processing to avoidsubstantial degradation of the therapeutic agent(s) are temperature,applied shear rate, applied shear stress, residence time of the mixturecontaining the therapeutic agent, and the technique by which thepolymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding a polyorthoester with therapeutic agent(s) and anyadditional additives to form a substantially homogenous mixture thereofmay be performed with any device known in the art and conventionallyused for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the various additives and a polyorthoester may be premixed priorto a final thermoplastic mixing and shaping process, if desired (e.g.,to prevent substantial degradation of the therapeutic agent among otherreasons).

For example, in various embodiments, a polyorthoester is precompoundedwith a radiographic agent (e.g., radio-opacifying agent) underconditions of temperature and mechanical shear that would result insubstantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the bupivacaine containing drug depot.Conversely, in another embodiment, the polyorthoester can beprecompounded with the therapeutic agent under conditions of reducedtemperature and mechanical shear. This precompounded material is thenmixed with, for example, a radio-opacifying agent, also under conditionsof reduced temperature and mechanical shear, and the resulting mixtureis shaped into the drug depot.

The conditions used to achieve a mixture of the polyorthoester andtherapeutic agent and other additives will depend on a number of factorsincluding, for example, the additive(s) used, as well as the type ofmixing device used.

In other embodiments, a polyorthoester and one or more therapeuticagents are premixed using non-thermoplastic techniques. For example, thepolyorthoester can be dissolved in a solvent system containing one ormore solvent species. Any desired agents (for example, aradio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing polymermatrix (the pre-existing drug depot can be formed using a variety oftechniques including solution and thermoplastic processing techniques,and it can comprise a variety of additives including a radio-opacifyingagent and/or viscosity enhancing agent), whereupon the therapeutic agentis imbibed on or in the polymer matrix. As above, the resulting solidmaterial can then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a polyorthoester, therapeutic agent(s) and radio-opacifyingagent(s). Co-extrusion may also be employed, which is a shaping processthat can be used to produce a drug depot comprising the same ordifferent layers or regions (for example, a structure comprising one ormore polymeric matrix layers or regions that have permeability to fluidsto allow immediate and/or sustained drug release). Multi-region depotscan also be formed by other processing and shaping techniques such asco-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet) is cooled. Examples of cooling processesinclude air cooling and/or immersion in a cooling bath. In someembodiments, a water bath is used to cool the extruded depot. However,where a water-soluble therapeutic agent such as bupivacaine is used, theimmersion time should be held to a minimum to avoid unnecessary loss oftherapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polyorthoester and then molding the depot tothe desired shape. In various embodiments, bupivacaine is used and mixedor sprayed with a polyorthoester, and the resulting depot may be formedby extrusion and dried.

In various embodiments, there is a pharmaceutical formulationcomprising: bupivacaine, wherein the bupivacaine comprises from about0.1 wt. % to about 70 wt. % of the formulation, and at least apolyorthoester. In some embodiments, the bupivacaine comprises fromabout 1 wt. % to about 50 wt. %, about 5 wt. % to about 50 wt. %, about10 wt. % to about 40 wt. % or about 15 wt. % to about 35 wt. % of theformulation. In some embodiments, the polyorthoester comprises fromabout 30 wt. % to about 99.9 wt. %, from about 50 wt. % to about 99 wt.%, from about 50 wt. % to about 95 wt. %, from about 60 wt. % to about90 wt. %, or from about 65 wt. % to about 85 wt. % of the formulation.

In various embodiments, the drug is present in the depot in the form ofa particle and the particle size is from about 0.1 to 1,000 microns indiameter, however, in various embodiments ranges from about 1 micron to250 microns, or 5 microns to 50 microns in diameter may be used. In someembodiments, the polyorthoester comprises at least 30 wt. %, at least 40wt. %, at least 50 wt. %, at least 60 wt. %, at least 70 wt. %, at least80 wt. % of the formulation, at least 85 wt. % of the formulation, atleast 90 wt. % of the formulation, at least 95 wt. % of the formulationor at least 99 wt. % of the formulation. It should be noted thatparticle size may be altered by techniques such as mortar and pestle,grinding, spray drying, jet-drying or jet milling.

In some embodiments, at least 75% of the drug particles have a size fromabout 1 micron to about 200 microns in diameter, more specifically fromabout 5 microns to about 50 microns in diameter. In some embodiments, atleast 85% of the particles have a size from about 1 micron to about 200microns in diameter, more specifically from about 5 microns to about 50microns in diameter. In some embodiments, at least 95% of the particleshave a size from about 1 micron to about 200 microns in diameter, morespecifically from about 5 microns to about 50 microns in diameter. Insome embodiments, all of the particles have a size from about 1 micronto about 200 microns in diameter, more specifically from about 5 micronsto about 50 microns in diameter.

In some embodiments, there is a pharmaceutical formulation comprising:bupivacaine, and comprises from about 0.1 wt. % to about 70 wt. % of theformulation, and at least a polyorthoester, wherein the polyorthoestercomprises at least 30 wt. % of the formulation. In some embodiments,there is a pharmaceutical formulation comprising: bupivacaine, wherein aportion of the bupivacaine is in the form of a salt, such as ahydrochloride salt, and a portion is in the form of bupivacaine base,and the mixture comprises about 0.1 wt. % to about 70 wt. % of theformulation, and at least a polyorthoester, wherein the polyorthoestercomprises at least 30 wt. % of the formulation.

In some embodiments, there are methods for treating chronic pain. Thesemethods comprise: administering a pharmaceutical composition to anorganism, wherein the pharmaceutical composition comprises from about0.1 wt. % to about 99 wt. % of the formulation comprising at least apolyorthoester and bupivacaine. In some embodiments, the loading is fromabout 5 wt. % to about 95 wt. %. In some embodiments, the loading isfrom about 10 wt. % to about 90 wt. %. In some embodiments, the loadingis from about 20 wt. % to about 80 wt. %.

In some embodiments, the formulations are rigid or slightly rigid withvarying length, widths, diameters, etc. For example, certainformulations may have a diameter of between about 0.5-3 mm and a lengthof about 50-100 mm.

In some embodiments, bupivacaine is released at a rate of 5 mg-50 mg perday for a period of at least thirty days. In some embodiments, thisrelease rate continues for, at least forty days, at least sixty days, atleast ninety days, at least one hundred days, at least one-hundred andthirty-five days, at least one-hundred and fifty days, or at least onehundred and eighty days. For some embodiments, 100-100,000 milligrams ofbupivacaine as formulated with a polyorthoester are implanted into aperson at or near a target site. It is important to limit the totaldaily dosage released to an amount less than that which would be harmfulto the organism.

The dosage may be from approximately 5 to approximately 50 mg/day.Additional dosages of bupivacaine include from approximately 10 mg/dayto approximately 40 mg/day, from approximately 15 mg/day toapproximately 35 mg/day, and from approximately 20 mg/day toapproximately 35 mg/day.

In one exemplary dosing regimen, a rat may be provided with sufficientbupivacaine in a biodegradable POE polymer to provide sustained releaseof 25 μg/day bupivacaine for 90 days. The total amount of bupivacainethat is administered over this time period would be approximately 2250μg. In another exemplary dosing regimen, a human is provided withsufficient bupivacaine in a biodegradable POE polymer to providesustained release of 50 mg/day bupivacaine for 90 days. The total amountof bupivacaine that is administered over this time period would beapproximately 4500 mg.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexamples, which are provided by way of illustration and are not intendedto limit the present invention unless specified.

EXAMPLES Example 1 Preparation of Polyorthoester

A polyorthoester having a molecular weight of 133 kDaltons wassynthesized by combining a stoichiometric mixture of3,9-diethylidene-2,4,8,10-tetraoxospiro[5,5]undecane (DETOSU) with amixture of diols including trans-1,4-cyclohexanedimethanol (54 mole %),1,6-hexanediol (45 mole %) and diethyl-tartrate (1 mole %). Bupivacainewas purchased from Orgamol (Switzerland). Methanol and acetone werepurchased from Sigma-Aldrich.

Methods: The following compositions were used to prepare apolyothoester: DETOSU at 34.9998 g (164.90 mmole),Trans-cyclohexanedimethanol at 12.5898 g (87.30 mmole), 1,6-hexanediolat 8.5965 g (72.75 mmole), Diethyltartrate at 0.3333 g (1.62 mmole),Para-toluenesulfonicacid at 2325 μl of a 1% (w/v) solution intetrahydrofuran (THF) and 315 ml of Tetrahydrofuran. In particular, a1000 ml round bottomed flask was pyro-leaned, washed with soap andwater, then insed with acetone, isopropanol, 0.1N NaOH and deionizedwater, and then oven-dried. All spatulas to be used for preparing thepolymer were washed and dried in the oven for at least 2 hours. A smallglass beaker was also washed and dried in the oven. All of the reactantswere weighed in a beaker. In a N₂ glove box, DETOSU was first weighedinto the beaker followed by the diols. 200 ml of THF was then added todissolve the solids and this solution was poured into the round bottomedflask. The rest of the THF was then added to the beaker again and theninto the flask. The solution was allowed to stir for 30 minutes. A 1%PTSA catalyst was then added to the solution at which point the solutionexothermed vigorously and became very thick. The stirring was thenstopped and the solution remained in the flask overnight. An IR scan ofa sample of the polymer solution was taken the next day and it showedthat the polymerization was complete (there was a minor peak at 3501cm⁻¹ but that was due to the thickness of the sample on the IR plate).

A blender was washed and dried in the oven for at least 8 hours. Atweezer was also dried. In the N₂ glove box, ˜500 ml of anhydrousmethanol was added to the blender. Four (4) drops of triethylamine werethen added to the waring blender. The polymer solution was then slowlypoured into a methanol solution. The polymer precipitated out easily.The precipitated polymer was then re-dissolved in minimal THF and pouredin fresh methanol. The polymer precipitated again and was then put in amylar boat and dried in the vacuum oven at full vacuum and 50° C. fortwo days. The POE polymer was then transferred to a dried jar.

Example 2 Preparation of POE-Bupivacaine Microspheres

Microspheres were prepared using a water/oil emulsion with avacuum-controlled hardening step. 850 mg of the polymer from Example 1,polyorthoester (54 mole % trans-cylcohexanedimethanol, 45%1,6-hexanediol and 1% diethyltartrate) was dissolved in methylenechloride along with bupivacaine (150-mg) at a solids concentration of1-g per 12-ml. The solution was then filtered through a 0.2 μm PTFEsyringe filter. The polymer/drug solution, 12-ml, was added slowly over1 minute into a 120-ml jar containing 60-ml of a 10 mM Trizma® basebuffer at pH 8.5 with 1% (w/v) polyvinylalcohol (Sigma-Aldrich) whilebeing mixed at 6,000 rpm with an IKA Ultra-Turrax T-18 high-shear mixer.The solution was mixed for 2 minutes and then poured into a 250-ml roundbottom flask, followed by 20-ml of water used to rinse the jar. Theflask was immediately placed on a rotoevaporator and the pressure wasreduced from 700 mbar to 5 mbar over 45 minutes and held at 5 mbar for15 minutes. The hardened microsphere suspension was poured into two50-ml conical tubes and centrifuged at 1000 rpm for 2 minutes. Thesupernatant was poured off and the spheres from each tube weretransferred to a single 50-ml conical tube and rinsed with 45-ml ofwater, centrifuged again, and the supernatant was poured off. This wasrepeated 2 more times and the spheres were then resuspended in 7-ml ofwater and frozen in liquid nitrogen. The frozen suspension waslyophilized for 24 hours and then transferred to a vacuum oven at 25° C.and dried for 1 week. The microspheres had a mean particle size of 19microns in diameter, measured with a Horiba LA-950 particle sizeanalyzer.

Example 3 In-vitro Release of Bupivicaine

Drug elution of bupivacaine from the microspheres described in Example 2was measured using a pouch method. The pouch method involved adding˜15-mg of the spheres described in Example 2 to a ¾″ by ¾″ nylon pouchwith a 5-micron mesh size. The pouch was prepared by heating sealing 3sides of the nylon mesh, adding the spheres, and then heat sealing thefinal side of the pouch. Two sets of pouches were created. The firstpouch set (Pouch 1) was then placed in 10-ml of phosphate bufferedsaline pH 7.4 contained in a vial and placed in an incubator/shaker at37° C. and 100 RPM. The second pouch set (Pouch 2) was placed in 10-mlof phosphate buffered saline/0.5% sodium dodecyl sulfate (SDS) pH 7.4contained in a vial and placed in an incubator/shaker at 37° C. and 100RPM. Sampling was performed by removing 8-ml of media with a pipette andthen adding 8-ml of fresh media to the vial. The samples were thenreturned to the incubator/shaker. Sampling of the first pouch wasperformed at 0, 1, 3, 7, 14, 21, 28, 38, 50, 64, 78, 92 and 129 days.Sampling of the second pouch was performed at 0, 1, 3, 7, 14, 21, 28,38, 50 and 66 days. Drug concentrations in the elution media weremeasured by HPLC with UV detection.

FIG. 1 shows the cumulative release of bupivacaine (normalized to a 100mg dose of microspheres) over time for Pouch 1 of the formulationdescribed above. FIG. 2 shows the % release of bupivacaine from Pouch 1of the formulation described above. FIG. 3 shows the cumulative releaseof bupivacaine (normalized to a 100 mg dose of microspheres) over timefor Pouch 2 of the formulation described above. FIG. 4 shows the %release of bupivacaine from Pouch 2 of the formulation described above.

Example 4 Epidural Infusion of Bupivacaine in a Rat Model of BladderPain

An animal model that has been used frequently to study pelvic painconditions is a rat model of bladder pain. In this model, a female ratwas lightly anesthetized with isoflurane and a transurethral catheterwas placed into the bladder. The catheter was connected to a pressuretransducer so that the pressure within the bladder could be continuouslymonitored and recorded over time. Fluid was continuously infused intothe bladder using a syringe pump at a rate of 0.1 mL/min to cause thebladder to contract repeatedly each time it became full. This isreferred to as a volume-evoked micturition reflex or contraction. Arepeated series of bladder contractions (pressure spikes) over time wascollected using this method. To mimic normal bladder activity, 0.9%saline was infused into the bladder; to mimic painful bladder activity,a dilute solution of acetic acid (0.5%) was infused into the bladder.Acetic acid infusion produced a marked increase in the frequency ofbladder contractions. In human patients that suffer from interstitialcystitis, a common form of pelvic pain, increased frequency of urinationand urinary urgency are common clinical symptoms. As depicted in FIGS. 5and 6, the baseline (BL) frequency of bladder contraction reflexes wasmarkedly increased (approximately 2-fold) during acetic acid infusion(FIG. 6) relative to the frequency observed during saline infusion (FIG.5, 0.566±0.045 vs. 0.295±0.035 reflexes per min).

In order to evaluate the effects of epidurally administered analgesicson normal and painful bladder activity (frequency of reflex bladdercontractions), test drugs were continuously administered via an epiduralcatheter with the tip placed in the mid-lumbar epidural space. Theproximal catheter was connected to an implanted osmotic mini pump sothat drug solution could be continuously infused. In the experimentsdepicted in FIGS. 5 and 6, the baseline bladder activity was measuredbefore implanting the epidural infusion system, the infusion system wasimplanted on day 0 and cystometrograms were recorded on threeconsecutive days during which bupivacaine (25 μg/day) was infused intothe lumbar epidural space. FIG. 5 indicates that epidural bupivacaineproduced minimal effects on normal bladder activity measured duringsaline infusion on day 1. On days two and three, bupivacaine did producestatistically significant reductions in the contraction rate relative tothe baseline reflex contraction rate.

FIG. 6 shows the pronounced effects of epidural bupivacaine infusion (25μg/day) on the frequency of bladder contraction reflexes measured duringacetic acid infusion into the bladder. As noted previously noted, thebaseline (BL) frequency of contractions during acetic acid infusion issignificantly higher than during saline infusion. Despite the increasein bladder activity, epidural infusion of bupivacaine significantlyreduced the frequency of bladder contraction reflexes on all three daysduring which it was infused. Bupivacaine at 25 μg/day reduced aceticacid induced bladder hypermotility by approximately 3 fold on days 2 and3. The frequency of bladder contraction observed during acetic acidinfusion and epidural bupivacaine administration was similar to thebaseline bladder activity measured during saline infusion (0.206±0.046day 3 acetic acid and epidural bupivacaine vs 0.295±0.035 baselinesaline).

Example 5 Preparation of Spray Dried Bupivacaine

In some embodiments, the bupivacaine is formulated with the POE as aparticle. It may be desired to have the particles within a desired sizerange. This can be accomplished by dissolving the bupivacaine in anappropriate solvent and spray drying the solution using methods andapparatus known to those of skill in the art.

For example, bupivacaine is dissolved in methylene chloride to yield asolution. The solution is spray dried in a Buchi B-290 Mini Spray Dryer(Buchi Laboratorium AG, Switzerland) using a 120 kHz Sono-Tek ultrasonicnozzle (Sono-Tek Corp., Milton, N.Y.). Exemplary processing parametersinclude: inlet temp. (40° C.), aspirator (80%), nitrogen inlet (50 mm),spray flow rate (80 mL/hr) and ultrasonic generator (0.8 watts). Thespray dried powder is collected and dried, such as for an additional 24hours at 70° C. and 15 mmHg vacuum.

Example 6 Preparation of Melt Extruded Rods

In some embodiments, the bupivacaine is melt extruded with the POE. Thiscan be accomplished by using methods and apparatus known to those ofskill in the art.

For example, several formulations having bupivacaine drug loadings of 5%(w/w), 10% (w/w), 20% (w/w), 30% (w/w), 40% (w/w) and 50% (w/w) areprepared for melt extrusion with POE described in Example 1. Eachformulation contains POE polymer ground into powder using a Retsch(Retsch GmbH, Germany) rotor mill with an 80 micrometer sieve filter andspray dried bupivacaine as described in Example 5. All formulations aredry mixed with a spatula prior to being fed into a Haake Mini-Lab twinscrew extruder (Thermo Fischer Scientific, Waltham, Mass.) set at 120°C. and 30 RPM. The rods are extruded out of a 0.75 mm diameter die andpulled by hand to obtain a final diameter of ˜0.7-0.8 mm.

The rods are then cut with a razor blade to desired length depending onthe corresponding drug loadings. Pellets from each formulation areplaced in 20 mL scintillation vials for drug elution testing. In-vitroelution studies are carried out at 37° C. in phosphate-buffered saline(PBS, pH 7.4). In particular, the pellets are incubated in 5 mL ofphosphate buffered saline pH 7.4 (Hyclone, 0.0067M) at 37° C. under mildagitation. At pre-selected times over a 135 day period, the buffer isremoved for analysis and replaced with fresh buffer medium. The drugcontent is quantified at 238 nm by a Molecular Devices SpectraMax M2(Sunnyvale, Calif.) plate reader.

Example 7 Preparation of Spray Dried POE-Bupivacaine Microparticles

In some embodiments, the bupivacaine and POE are spray dried together toform microparticles. This can be accomplished as described above inExample 5 using methods and apparatus known to those of skill in theart.

For example, bupivacaine and POE are dissolved together in methylenechloride to yield a solution. The solution is spray dried in a BuchiB-290 Mini Spray Dryer (Buchi Laboratorium AG, Switzerland) using a 120kHz Sono-Tek ultrasonic nozzle (Sono-Tek Corp., Milton, N.Y.). Exemplaryprocessing parameters include: inlet temp. (40° C.), aspirator (80%),nitrogen inlet (50 mm), spray flow rate (80 mL/hr) and ultrasonicgenerator (0.8 watts). The spray dried powder is collected and dried,such as for an additional 24 hours at 70° C. and 15 mmHg vacuum.

Example 8 Epidural Administration of POE-Bupivacaine Depot in a RatModel of Bladder Pain

In some embodiments, the drug depot is implanted in a mammal. This canbe accomplished by using methods and apparatus known to those of skillin the art and described herein.

For example, an animal model that has been used frequently to studypelvic pain conditions is a rat model of bladder pain as described abovein Example 4.

A drug depot designed to deliver 25 μg/day of bupivacaine is epidurallyadministered to the mid-lumbar epidural space. The baseline bladderactivity is measured before implanting the epidural drug depot, the drugdepot system is implanted on day 0 and cystometrograms are recordedperiodically over 135 days during which bupivacaine (25 μg/day) isreleased into the lumbar epidural space.

It will be apparent to those skilled in the art that variousmodifications and variations can be made to various embodimentsdescribed herein without departing from the spirit or scope of theteachings herein. Thus, it is intended that various embodiments coverother modifications and variations of various embodiments within thescope of the present teachings.

1. An implantable drug depot useful for reducing, preventing or treatingpain in a patient in need of such treatment, the drug depot comprising apolyorthoester and bupivacaine, the drug depot adapted to beadministered intraspinally in the patient to reduce, prevent or treatpain, wherein the drug depot is capable of releasing bupivacaine for aperiod of at least 30 days after administration.
 2. An implantable drugdepot according to claim 1, wherein the polyorthoester is capable ofdegrading in 200 days or less after the drug depot is administered atthe site.
 3. An implantable drug depot according to claim 1, wherein thebupivacaine is capable of being released for a period of 30 to 180 daysafter administration.
 4. An implantable drug depot according to claim 1,wherein the bupivacaine is present in an amount of about 1 to about 50wt. % of the drug depot and the polyorthoester is present in an amountof about 50 to about 99 wt. % of the drug depot.
 5. An implantable drugdepot according to claim 1, wherein the depot is in the form ofmicrospheres having an average diameter from about 1 micron to about 150microns.
 6. An implantable drug depot according to claim 1, wherein thedepot further comprises a radiographic marker.
 7. An implantable drugdepot according to claim 1, wherein the bupivacaine is present in thedepot in the form of particles, wherein at least 75% of the particleshave a size from about 5 microns to about 50 microns in diameter.
 8. Animplantable drug depot according to claim 1, wherein the polyorthoestercomprises at least 70 wt. % of the drug depot.
 9. An implantable drugdepot according to claim 1, further comprising one or more ofpolyaspirin, polyphosphazene, polyanhydride; polyketal, collagen,starch, pre-gelatinized starch, hyaluronic acid, chitosan, gelatin,alginate, albumin, fibrin, vitamin E analog, d-alpha tocopherylsuccinate, poly-ε-caprolactone, dextran, polyvinylpyrrolidone, polyvinylalcohol, PEGT-PBT copolymer, PEO-PPO-PEO, sucrose acetate isobutyrate, adifferent polyorthoester or a combination thereof.
 10. An implantabledrug depot according to claim 1, wherein the bupivacaine is in the formof a hydrochloride salt or a mixture of hydrochloride salt and freebase.
 11. An implantable drug depot according to claim 1, wherein thedrug depot further comprises baclofen.
 12. A method for treating pain,wherein the method comprises implanting a drug depot intraspinally in anorganism, wherein the drug depot comprises bupivacaine in an amount fromabout 1 wt. % to about 50 wt. % of the drug depot, and a polyorthoester.13. A method according to claim 12, wherein the bupivacaine comprisesfrom about 10 wt. % to about 40 wt. % of the drug depot.
 14. A methodaccording to claim 12, wherein the bupivacaine is released in an amountfor a period of 30 to 135 days.
 15. A method according to claim 12,wherein the drug depot is a ribbon.
 16. A method according to claim 12,wherein the polyorthoester comprises at least 70 wt. % of the drugdepot.
 17. A method according to claim 12, wherein the depot is in theform of microspheres having an average diameter from about 1 micron toabout 500 microns.
 18. A method according to claim 12, wherein thebupivacaine is present in the depot in the form of particles, wherein atleast 75% of the particles have a size from about 5 microns to about 50microns in diameter.
 19. A method according to claim 12, wherein thedrug depot further comprises a radiographic marker.
 20. A method ofmaking an implantable drug depot, the method comprising combining apolyorthoester and bupivacaine and forming the implantable drug depotfrom the combination.